RESEARCH ARTICLE

Selective Serotonin Reuptake Inhibitors and Violent Crime: A Cohort Study Yasmina Molero1, Paul Lichtenstein2, Johan Zetterqvist2, Clara Hellner Gumpert1, Seena Fazel3* 1 Center for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden, 2 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, 3 Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom * [email protected]

Abstract Background OPEN ACCESS Citation: Molero Y, Lichtenstein P, Zetterqvist J, Gumpert CH, Fazel S (2015) Selective Serotonin Reuptake Inhibitors and Violent Crime: A Cohort Study. PLoS Med 12(9): e1001875. doi:10.1371/ journal.pmed.1001875 Academic Editor: Alexander C. Tsai, Massachusetts General Hospital and Harvard Medical School, Boston, United States of America Received: March 31, 2015 Accepted: August 5, 2015 Published: September 15, 2015 Copyright: © 2015 Molero et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: SF is supported by the Wellcome Trust [095806]. YM and CHG are supported by Karolinska Institutet. JZ and PL are supported by grants from the Swedish Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: SF has received travelling

Although selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, associations with violence are uncertain.

Methods and Findings From Swedish national registers we extracted information on 856,493 individuals who were prescribed SSRIs, and subsequent violent crimes during 2006 through 2009. We used stratified Cox regression analyses to compare the rate of violent crime while individuals were prescribed these medications with the rate in the same individuals while not receiving medication. Adjustments were made for other psychotropic medications. Information on all medications was extracted from the Swedish Prescribed Drug Register, with complete national data on all dispensed medications. Information on violent crime convictions was extracted from the Swedish national crime register. Using within-individual models, there was an overall association between SSRIs and violent crime convictions (hazard ratio [HR] = 1.19, 95% CI 1.08–1.32, p < 0.001, absolute risk = 1.0%). With age stratification, there was a significant association between SSRIs and violent crime convictions for individuals aged 15 to 24 y (HR = 1.43, 95% CI 1.19–1.73, p < 0.001, absolute risk = 3.0%). However, there were no significant associations in those aged 25–34 y (HR = 1.20, 95% CI 0.95–1.52, p = 0.125, absolute risk = 1.6%), in those aged 35–44 y (HR = 1.06, 95% CI 0.83–1.35, p = 0.666, absolute risk = 1.2%), or in those aged 45 y or older (HR = 1.07, 95% CI 0.84–1.35, p = 0.594, absolute risk = 0.3%). Associations in those aged 15 to 24 y were also found for violent crime arrests with preliminary investigations (HR = 1.28, 95% CI 1.16–1.41, p < 0.001), non-violent crime convictions (HR = 1.22, 95% CI 1.10–1.34, p < 0.001), non-violent crime arrests (HR = 1.13, 95% CI 1.07–1.20, p < 0.001), non-fatal injuries from accidents (HR = 1.29, 95% CI 1.22–1.36, p < 0.001), and emergency inpatient or outpatient treatment for alcohol intoxication or misuse (HR = 1.98, 95% CI 1.76–2.21, p < 0.001). With age and sex stratification, there was a significant association between SSRIs and violent crime convictions for males aged 15 to 24 y (HR = 1.40, 95% CI 1.13–1.73, p = 0.002) and females aged

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expenses from Janssen to attend a Janssenorganized conference on the effectiveness of antipsychotics where he presented a Wellcomefunded study on antipsychotics that had been published in the Lancet (Janssen do not currently produce an antidepressant). The speaker's fee was donated to charity. None of the other authors report competing interests. Abbreviations: DDD, defined daily dose; HR, hazard ratio; SSRI, selective serotonin reuptake inhibitor.

15 to 24 y (HR = 1.75, 95% CI 1.08–2.84, p = 0.023). However, there were no significant associations in those aged 25 y or older. One important limitation is that we were unable to fully account for time-varying factors.

Conclusions The association between SSRIs and violent crime convictions and violent crime arrests varied by age group. The increased risk we found in young people needs validation in other studies.

Introduction Selective serotonin reuptake inhibitors (SSRIs) are among the most widely prescribed psychiatric medications in many countries [1–6]. At the same time, concerns about their adverse effects, including suicide and violence, have been widely discussed and remain controversial. Observational and trial data have shown that although SSRIs appear not to elevate the risk for suicidal behaviour in adults, they may increase the risk of suicide ideation in children, adolescents, and young adults. This weak age-related association is consistent across studies [7–11] but inconsistently supported by ecological data [12–15]. Despite a number of legal cases linking SSRIs and violent behaviour [16], empirical research on the association is limited and inconclusive. Ecological studies suggest that increased SSRI prescriptions have been associated with decreases in violent crimes in the US [17] and lethal violence in the Netherlands [18]. In contrast, an expert review of clinical trials concluded that there was an excess of violence in both adults and children on SSRIs compared with placebo [16]. Furthermore, drug safety (or pharmacovigilance) data have shown a disproportionate association between SSRIs and violent behaviours [19] and serious violent acts [20], and an observational study found an association of work-related violence with antidepressant purchases [21]. However, these study designs are limited: findings from ecological data fail to relate the use of SSRIs at the individual level and are liable to be influenced by secular changes, including legislation, reporting of violence, and unaccounted changes in the impact of other risk factors such as drug and alcohol use [15,22]. Pharmacovigilance data are subject to reporting bias, changes in patient awareness about adverse outcomes, confounding by indication, and failure to account for exposure to other medications [23]. Pharmacoepidemiological studies provide one approach to deal with these limitations [12,23]. Our objective was thus to investigate the association between SSRIs and violence outcomes by linking data from Swedish national registers on individual SSRI prescriptions, use of other psychotropic drugs, and violent crimes in a large population-based cohort. We have primarily used a “within-individual” design [24–27], where the risk of violent crime is determined when an individual is taking an SSRI as compared to when the same person is not. Using this design, all time-invariant factors (i.e., genetic factors, all factors before the start of follow-up, and factors that remain constant during follow-up) are accounted for; thus, this design more fully adjusts for unmeasured time-invariant confounding and confounding by indication than other observational designs, but does not account for time-varying factors such as symptom severity. Our null hypothesis was that no associations between SSRI medication and violent outcomes would be demonstrated using a within-individual design, including in different age groups.

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Methods In the total population of Sweden aged 15 y or older in 2006 (n = 7,917,854) and residing in Sweden during follow-up (January 1, 2006, to December 31, 2009), we identified 856,493 individuals who were prescribed SSRI treatment. Information on individuals receiving SSRI treatment was collected from Swedish population-based registers with national coverage, and registers were linked using each individual’s unique identification number. The project was approved by the ethics committee at Karolinska Institutet (2005/4:5).

Measures SSRI treatment. Information on medication and the date prescriptions were dispensed was extracted from the Swedish Prescribed Drug Register, with complete national data on all prescribed and dispensed medical drugs from all pharmacies in Sweden since July 2005 [28]. A previous comparison between post-mortem toxicology and SSRI purchases in the Swedish Prescribed Drug Register indicated good medication compliance [29]. In our initial analysis, we included all individuals with dispensed SSRI prescriptions. However, as prescriptions are typically restricted to at most 3 mo and we wanted to restrict the sample to those adherent to SSRIs, individuals with a single SSRI prescription within a 6-mo period were excluded from stratified and sensitivity analyses as no assumptions could be made about their medication adherence. A separate analysis was also carried out including only individuals with a single dispensed prescription. A treatment period was thus defined as a series of SSRI prescriptions with no more than 6 mo between two consecutive prescriptions. The start of a treatment period was defined as the date an SSRI prescription was first dispensed during our follow-up. The end of a treatment period was defined as the date that the last SSRI prescription in that treatment period was dispensed. Periods of more than 6 mo between prescriptions were considered non-treatment periods. A new treatment period was considered to have started at the first date of the next series of consecutive prescriptions (see S1 Methods for details on SSRI medications). For individuals with a single prescription, the start of their treatment period was defined as the date their prescription was dispensed, and the end of that treatment period was defined as 14 d after the prescription was dispensed. Other psychotropic medications. Adjustments were made for concurrent psychotropic medications other than SSRIs, which included antipsychotics, hypnotics, sedatives, anxiolytics, drugs used in addictive disorders, mood stabilisers, antiepileptics, and antidepressant medications other than SSRIs (venlafaxine, duloxetine, tricyclics, heterocyclics, mirtazapine, nonselective monoamine oxidase inhibitors, moclobemide, and bupropion). Treatment periods were defined in the same manner as SSRI treatment periods (see S1 Methods for details). Violent crimes. Information on convictions for violent crimes for individuals aged 15 y and older (the age of criminal responsibility) was extracted from the Swedish national crime register. Violent crimes were defined as crimes against persons as per previous work [30], and included attempted, completed, and aggravated forms of homicide, manslaughter, unlawful threats, harassment, robbery, arson, assault, assault on an official, kidnapping, stalking, coercion, and all sexual offences (see S1 Methods for more details). Alternative outcomes. Examinations of individual SSRIs and alternative outcomes were also carried out, including (1) convictions for substance-related crimes, (2) convictions for non-violent crimes, (3) arrests with preliminary investigations (hereafter “arrests”, as distinct from convictions; described as “suspicions” in the Swedish crime register) for violent crimes, (4) arrests for substance-related crimes, (5) arrests for non-violent crimes, (6) non-fatal injuries (hospitalisations) from accidents; (7) emergency inpatient or outpatient treatment for alcohol

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intoxication or misuse, (8) and psychiatric hospitalisations (see S1 Methods for details on alternative outcomes).

Statistical Analyses Individuals were followed from January 1, 2006, to December 31, 2009, and follow-up was adjusted for migration, periods in prison or institutional youth care, hospitalisation, and death through linkage to the Swedish migration, prison, patient, and cause of death registers. Unobservable time, i.e., time abroad, in prison, or in hospital, was removed (truncated) from the follow-up time. Time after hospital discharge, release from prison, or immigration was added to the observable cohort again. A between-individual Cox proportional hazards regression compared the average rate of violent crime convictions during SSRI medication with the rate during non-medication for all individuals. In this analysis, follow-up period was split into the period before the first outcome, periods between outcomes, and the period after the last outcome. Time at risk was measured from the start of each period, and medication was used as a time-varying covariate. Robust standard errors were calculated to account for correlations between periods within the same individual. This analysis was adjusted for sex and age. The principal analyses were within-individual stratified Cox proportional hazards regressions, with each individual entering as a separate stratum in the analysis and serving as his/her own control. The obtained hazard ratio (HR) is thus adjusted for (i.e., stratified by) all potential time-invariant confounders within each individual. To adjust for age, which is a time-varying potential confounder, age was added to the model as a time-varying covariate, with one factor for each whole year. In the within-individual stratified Cox proportional hazards regression, only individuals who changed medication status contributed directly to the estimate. All other individuals contributed indirectly through the estimates of other covariates. Since the covariates in the within-individual stratified Cox proportional hazards regression were time-varying, we did not test for the proportional hazards assumption. More information on this approach is provided in [31]; this approach has been applied in studies of attention deficit hyperactivity disorder medication, antipsychotics, and mood stabilisers [24–27]. To ensure that outcomes were measured appropriately, all crimes were included from the date of perpetration (rather than conviction), and those with uncertain date of perpetration were excluded from the analyses, resulting in the exclusion of 1.3% (1,241) of violent crime convictions, 1.0% (9,108) of nonviolent crime convictions, and 1.8% (5,187) of substance-related convictions during the period from 2006 to 2009. To test for confounding by other psychotropic medications, we first adjusted for concurrent exposure to other psychotropic medications as a time-varying covariate. Then we excluded individuals with other psychotropic medications during follow-up from the within-individual stratified Cox proportional hazards regression. Analyses were also stratified by sex, by age (from age 15 y, the age of criminal responsibility, in 10-y bands [32] up to age 44 y; the age bands for ages 45 y and over were combined as event rates were low), and by type of SSRI medication (fluoxetine, citalopram, paroxetine, sertraline, or escitalopram). To estimate cumulative exposure to SSRIs, the defined daily dose (DDD) of SSRI medication [33] was calculated through summing dispensed medication and then dividing the sum by the number of days in the treatment period. DDDs were categorised into four groups; (1) no exposure, (2) low SSRI exposure (2 DDD/day). Sensitivity analyses. In sensitivity analyses, within-individual stratified Cox proportional hazards regressions were carried out with the following alternative outcomes: convictions for

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non-violent crimes, convictions for substance-related crimes, arrests for violent crimes, arrests for non-violent crimes, arrests for substance-related crimes, non-fatal injuries from accidents, emergency treatment for alcohol intoxication or misuse, and psychiatric hospitalisations. Furthermore, each SSRI medication was analysed separately, and periods of using of two or more SSRI medications were excluded to adjust for switching effects between SSRI medications. Furthermore, all SSRIs were entered in the same model as covariates to adjust for concurrent use of other SSRIs. Analyses were also stratified by type of SSRI medication with violent crime arrests as an alternative outcome. Additionally, other antidepressants (venlafaxine, duloxetine, tricyclics, heterocyclics, mirtazapine, moclobemide, and bupropion) were used as an alternative exposure for violent crime convictions. Further sensitivity analyses were carried out to test for non-specific treatment effects where diuretics were used as an alternative exposure for violent crime convictions to test the model. For individuals who started SSRI treatment after being convicted of a violent crime, the number of days between the date of committing the crime and the start of SSRI treatment was calculated. To exclude the possibility of reverse causation, i.e., if committing a violent crime increased the probability of subsequent SSRI treatment, new within-individual stratified Cox proportional hazards regressions were carried out excluding from the analysis all individuals who received SSRI treatment within 7, 14, 30, or 60 d after committing a violent crime. Finally, the robustness of results was tested by undertaking four alternative analyses. First, a conditional Poisson regression examined how changes in medication exposure were associated with changes in violent crime convictions within the same person, thus adjusting for timeinvariant confounders. Second, we repeated the main models with different definitions of a treatment period: (1) a series of SSRI prescriptions with no more than 3 mo between two consecutive prescriptions and (2) a series of SSRI prescriptions with no more than 4 mo between two consecutive prescriptions. Third, we tested for delayed onset of action of SSRIs by setting the first day of the treatment period to 8 wk after the date of the first dispensed prescription. Fourth, we tested for SSRI discontinuation effects by extending the end of the treatment period to 3 wk and 12 wk after the date that the last SSRI prescription in a treatment period was dispensed. SAS version 9.4 (SAS Institute) was used for all analyses, except for the conditional Poisson regression, for which STATA 13.1 (StataCorp) was used. For SAS, software function “proc phreg” was used for both stratified and marginal Cox regressions, and for STATA, software function “xtpoisson” was used for the conditional Poisson regression. STROBE guidelines were followed (S1 STROBE).

Results Sample Description Of 7,917,854 individuals in the general population investigated (individuals in Sweden aged 15 y or older in 2006), 856,493 (10.8%) were prescribed SSRIs during the time period 2006–2009, or 14.1% of all women and 7.5% of all men in the investigated population (see Table 1 for background characteristics). Of those prescribed SSRIs, 9.9% were aged 15–24 y, 12.7% were aged 25–34 y, 16.5% were aged 35–44 y, 15.6% were aged 45–54 y, 15.5% were aged 55–64 y, and 29.7% were aged 65 y or over at baseline in 2006. In the SSRI cohort, 8,377 individuals (1.0%) were convicted of a violent crime during the period 2006–2009. Among the individuals who were prescribed SSRI treatment, 65,862 individuals were prescribed fluoxetine, 389,857 citalopram, 46,615 paroxetine, 215,873 sertraline, 1,198 fluvoxamine, and 84,934 escitalopram.

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Table 1. Characteristics at baseline and during follow-up for SSRI-medicated and non-medicated individuals in a population sample in Sweden 2006–2009. Non-Medicated

SSRI-Medicatedǂ

89.2% (7,061,361)

10.8% (856,493)

Women

48.8% (3,443,970)

65.9% (564,278)

Men

51.2% (3,617,391)

34.1% (292,215)

15 to 24 y

20.4% (1,439,183)

9.9% (84,647)

25 to 34 y

14.7% (1,039,843)

12.7% (108,928)

35 to 44 y

16.2% (1,144,303)

16.5% (141,375)

45 to 54 y

14.6% (1,029,305)

15.6% (133,996)

55 to 64 y

15.3% (1,082,914)

15.5% (132,995)

65 y and over

18.8% (1,325,813)

29.7% (254,552)

Characteristic

Characteristics at baseline Sex

Age

Lifetime psychiatric diagnoses Psychotic disorder

0.9% (63,242)

3.3% (27,838)

Mood disorder

2.0% (143,910)

23.2% (198,366)

Anxiety, dissociative, stress-related, or somatoform disorder

2.6% (180,735)

20.3% (173,665)

Eating disorder

0.2% (10,965)

1.2% (10,414)

Substance (alcohol and drug) use disorder

2.7% (193,164)

9.1% (77,746)

Characteristics during follow-up Other psychotropic medications Antipsychotic

0.3% (24,515)

0.9% (7,998)

Hypnotic, sedative, or anxiolytic

11.5% (814,717)

37.4% (319,987)

Drug used in addictive disorders

1.1% (74,736)

2.5% (21,494)

Mood stabiliser

0.8% (58,519)

2.5% (21,151)

Antiepileptic medication

1.0% (74,474)

3.4% (28,722)

Venlafaxine

0.5% (32,911)

3.0% (25,906)

Duloxetine

0.3% (18,135)

2.2% (18,871)

Tricyclic

1.7% (116,963)

4.7% (40,272)

Heterocyclic

0.2% (11,622)

2.3% (19,770)

Mirtazapine

1.4% (95,223)

14.0% (119,757)

Non-selective monoamine oxidase inhibitor

Selective Serotonin Reuptake Inhibitors and Violent Crime: A Cohort Study.

Although selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, associations with violence are uncertain...
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